Monday, April 7, 2014

The Molecular Mechanism of Sleeve Gastrectomy

sharma-obesity-verticalsleevegastrectomyIn recent year, vertical sleeve gastrectomy (VSG), which involves removing large parts of the stomach, thereby reducing it to the size of a small banana, has gained in popularity in bariatric surgery.

Although slightly less efficacious, it is a far simpler procedure to perform than the “classic” Roux-en-Y gastric bypass.

According to popular wisdom, the reason why VSG works has to do with mechanically reducing the volume of the stomach (thereby creating a physical “restriction”), whereby effect on gastric ghrelin secretion may or may not also play a role in reducing hunger (the science on this is somewhat unclear).

Now, a paper by Karen Ryan and colleagues from the University of Cincinnati, published in Nature, provides a completely new explanation for the molecular mechanism by which this surgery appears to work.

The study was prompted by the observation that VBG leads to profound changes in circulating bile acids. Bile acids are now known to bind to a nuclear receptor (farsenoid-X-receptor or FXR for short) which plays an important role in fat and glucose metabolism.

Using a rather elegant series of studies in mice, Ryan and colleagues demonstrate that the weight loss effect of sleeve gastrectomy has little to do with reducing the size of the stomach. Rather, almost all of its effect on body weight appears to be mediated by the effect of this surgery on circulating bile acids and accompanying changes in gut microbial flora.

The researchers also clearly demonstrate that much of the weight loss with SVG is dependent on a functional FXR, without which (as in FXR knockout mice) the surgery has little effect on body weight or glucose metabolism.

This demonstration of the importance of bile acids and FXR signalling as an important molecular mechanism for why VSG actually works is important because it means that this surgery could possibly be mimicked by pharmacological interventions that target bile acid and/or FXR.

In fact drugs that stimulate FXR (e.g. obeticholic acid) are already being considered for other indications including fatty liver disease and type 2 diabetes.

Given the remarkable efficacy of VSG surgery, the possibility of providing the same benefits in a pill are clearly attractive.

@DrSharma
Edmonton, AB

ResearchBlogging.orgRyan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, Wilson-Pérez HE, Sandoval DA, Kohli R, Bäckhed F, & Seeley RJ (2014). FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature PMID: 24670636

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Wednesday, April 2, 2014

Trotting Out STAMPEDE

sharma-obesity-blood-sugar-testing2In the obesity world, this week’s big news is the publication of the three year results of the STAMPEDE trial in the New England Journal of Medicine.

As a regular reader, you may recall my previous post on this randomised controlled trial of bariatric surgery for the treatment of type 2 diabetes.

STAMPEDE involved the randomisation of 150 obese patients with uncontrolled type 2 diabetes to either intensive medical therapy alone or intensive medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy.

Rather than weight loss, the primary end point of STAMPEDE was a glycated hemoglobin (HbA1C) level of 6.0% or less (from a mean baseline of 9.3%).

For the 91% of the patients who completed 36 months of follow-up at three years, 5% of the patients in the medical-therapy group achieved an HbA1c of 6.0% compared to 38% of those in the gastric-bypass group and 24% of those in the sleeve-gastrectomy group.

In addition, surgically treated subjects overall had far lesser need for glucose-lowering medications, including insulin than those receiving medical treatment.

Weight was reduced by 20-25% in the surgical groups compared to a 4% weight loss in the medical arm of the study.

Quality-of-life was also significantly better in the two surgical groups than in the medical-therapy group.

There were no major late surgical complications.

By any reasonable standard, there cannot be any remaining doubt in anyone’s mind that surgical treatment for type 2 diabetes is vastly superior to anything that medical treatment has to offer.

Diabetologists and, in fact, all physicians, diabetes educators, dietitians and other health professionals, who fail to inform and counsel their type 2 patients with regard to surgical treatment options for their condition, risk being accused of malpractice.

Whether patients want surgery for diabetes or not is ultimately their choice – being informed of the potential benefits of surgery should not be a matter of choice – it should be good clinical practice.

@DrSharma
Edmonton, AB

Disclaimer: I am NOT a surgeon!

ResearchBlogging.orgSchauer PR, Bhatt DL, Kirwan JP, Wolski K, Brethauer SA, Navaneethan SD, Aminian A, Pothier CE, Kim ES, Nissen SE, Kashyap SR, & the STAMPEDE Investigators (2014). Bariatric Surgery versus Intensive Medical Therapy for Diabetes – 3-Year Outcomes. The New England journal of medicine PMID: 24679060

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Thursday, March 27, 2014

Three Essential Ways in Which Melatonin Links to Energy Balance

sharma-obesity-pineal-glandAs a regular reader, you will be quite familiar with the emerging recognition of sleep (or rather lack thereof) as an important determinant of weight gain.

Melatonin, an evolutionary ancient molecule that, in mammals, is secreted from the pineal gland, is a hormone that plays a major role as a key regulator of the circadian cycle, along which  virtually all metabolic activities are coordinated.

A paper by José Cipolla-Neto and colleagues, published in the Journal of Pineal Research, provides a fascinating overview of how melatonin plays a significant role in energy metabolism.

Its first role relates to insulin secretion and action. Thus, melatonin is not only necessary for the proper synthesis and secretion of insulin, it also plays a role in the insulin-signalling pathway through its effects on GLUT4 receptors.

Secondly, as a powerful chronobiotic, it helps coordinate various metabolic processes so that the activity/feeding phase of the day is associated with higher insulin sensitivity whereas the rest/fasting phase is synchronized to lower insulin sensitivity.

Thirdly, melatonin plays an important role in regulating energy flow to and from fat stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue.

The paper discusses how the reduction in melatonin production, as seen during aging, shift-work or night-time light exposure can induce insulin resistance, glucose intolerance, sleep disturbance and metabolic circadian disorganization, which together can lead to weigh gain.

Thus, the available data supports the notion that melatonin replacement therapy may provide a novel strategy to influence metabolism, at least in people with disruptions in their melatonin system.

Clearly, these notions need to be tested in well-controlled randomised trials but there certainly appears to be ample data to suggest that such a trial may well be worthwhile.

If you have taken melatonin or prescribed it to your patients, I’d certainly like to hear about your experience.

@DrSharma
Edmonton, AB

Hat tip to Sukie for pointing me to this article.

ResearchBlogging.orgCipolla-Neto J, Amaral FG, Afeche SC, Tan DX, & Reiter RJ (2014). Melatonin, Energy Metabolism and Obesity: a Review. Journal of pineal research PMID: 24654916

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Wednesday, March 26, 2014

How The FTO Gene Affects Body Weight

sharma-obesity-dna_molecule9Body weight is one of the most heritable of physiological traits – in fact (believe it or not), it is just as heritable as body height.

Among the many genes associated with body weight, data for the FTO gene have been most consistent.

But these finding have puzzled researchers, as genetic manipulations of the coding regions of the FTO gene have large effects on body weight, without any apparent change in the function of this gene.

Now, a paper by Scott Smemo and colleagues, published in NATURE, suggests a mechanism for how variants of the FTO gene may affect body composition.

The answer lies in the way that the region of the FTO gene associated with obesity directly interacts with another gene IRX3, located a few megabases away on the same chromosome. This interaction appears conserved across species all the way back to the zebrafish.

Consistent with this finding, it turns out that the obesity-associated single nucleotide polymorphisms of the FTO gene are associated with changes in the expression of IRX3, but not FTO, in human brains.

Also consistent with this idea is the fact that IRX3-deficient mice have a 30% lower body weight, primarily due to less fat mass and an increase in basal metabolic rate with browning of white adipose tissue. The animals also appear resistant to the effects of a high-fat diet and appear protected against diabetes.

Furthermore, expression of a dominant-negative form of IRX3 in the hypothalamus reproduces the metabolic phenotypes of Irx3-deficient mice.

Thus, these findings suggest that FTO exerts its effect on body weight through its functional impact on the IRX3 gene, a gene that has so far not been linked to body weight regulation.

This is of particular significance, as IRX3 appears to be a “master gene” that controls the expression of other genes in many tissues including the brain and fat cells.

Given that variants of the FTO gene are frequent in the population and consistently linked to obesity (and type 2 diabetes), these findings may take us one step closer to a molecular target for anti-obesity interventions.

@DrSharma
Edmonton, AB
ResearchBlogging.orgSmemo S, Tena JJ, Kim KH, Gamazon ER, Sakabe NJ, Gómez-Marín C, Aneas I, Credidio FL, Sobreira DR, Wasserman NF, Lee JH, Puviindran V, Tam D, Shen M, Son JE, Vakili NA, Sung HK, Naranjo S, Acemel RD, Manzanares M, Nagy A, Cox NJ, Hui CC, Gomez-Skarmeta JL, & Nóbrega MA (2014). Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature, 507 (7492), 371-5 PMID: 24646999

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Wednesday, March 19, 2014

Can Testosterone Lead to Weight Loss in Hypogonadal Men?

sharma-obesity-impotenceLoss of male gonadal function has been associated with weight gain (particularly visceral adiposity) as well as metabolic disturbances including dyslipidemia and insulin resistance.

However, wether or not hormonal substitution with testosterone (T) ameliorates these metabolic abnormalities or even leads to weight loss remains controversial.

Now a 6-year observational study by Ahmad Haider and colleagues from Germany, published in the International Journal of Endocrinology, strongly suggests that this may well be the case.

The authors analysed data from two prospective longitudinal studies that included 156 obese hypogonadal men, aged between 41 and 73 years (mean 61.17 ± 6.18) with previously diagnosed type 2 diabetes, who were seeking urological consultation for various conditions such as erectile dysfunction, decreased libido, questions about their T status, or a variety of urological complaints.

All subjects  had subnormal plasma total T levels and at least mild symptoms of hypogonadism assessed by the Aging Males’ Symptoms scale (AMS).

Treatment was started with parenteral T undecanoate 1000 mg (Nebido, Bayer Pharma, Berlin, Germany), administered at baseline and 6 weeks and thereafter every 12 weeks for up to 72 months. Subjects were also given general advice on healthy eating and physical activity.

This treatment resulted in an increase in total T levels from 8.9 ± 1.99 nmol/L to above 16 nmol/L within the first year of therapy, and remained at this physiological level throughout the course of treatment.

This change in T levels was associated with a progressive 12 cm decrease in waist circumference and weight loss of about 17.5 Kg (15% of initial weight) with BMI dropping from 36.5 to 31.2 at year 6.

Concomitantly, fasting glucose declined from 7.06 to 5.59 mmol/L and HbA1c decreased from 8.08 to 6.14%.

There were also favourable changes in systolic and diastolic blood pressure, lipid profiles including triglycerides and total cholesterol:HDL ratio, as well as CRP and liver enzymes.

While general caution is in order given that there was no control group, these finding certainly strongly suggest a possible role for T-replacement therapy in hypogonadal males presenting with symptoms of hypogonadism and weight gain.

Clearly, the 15% weight loss is impressive and well-exceeds what is generally seen with pharmacological obesity treatments.

If nothing else, these observations should prompt the conduct of a well-designed randomised controlled trial to confirm the effect and safety of T replacement therapy for obesity in hypogonadal men.

@DrSharma
Edmonton, AB

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In The News

Diabetics in most need of bariatric surgery, university study finds

Oct. 18, 2013 – Ottawa Citizen: "Encouraging more men to consider bariatric surgery is also important, since it's the best treatment and can stop diabetic patients from needing insulin, said Dr. Arya Sharma, chair in obesity research and management at the University of Alberta." Read article

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